Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.

We conducted a genome-wide scan of SNPs to identify variants associated with length of survival in 1,331 individuals with esophageal squamous-cell carcinoma (ESCC), with associations validated in 2 independent sets including 1,962 individuals with this cancer. We identified rs1050631 in SLC39A6 as associated with the survival times of affected individuals, with the hazard ratio for death from ESCC in the combined sample being 1.30 (95% confidence interval (CI) = 1.19-1.43; P = 3.77 × 10(-8)). rs7242481, located in the 5' UTR of SLC39A6, disturbs a transcriptional repressor binding site and results in upregulation of SLC39A6 expression. Immunohistochemical staining of ESCC tissues showed that higher expression of SLC39A6 protein was correlated with shorter length of survival in individuals with advanced ESCC (P = 0.013). Knockdown of SLC39A6 expression suppressed proliferation and invasion in ESCC cells. These results suggest that SLC39A6 has an important role in the prognosis of ESCC and may be a potential therapeutic target.

IntroductionThough a meta-analysis reported the effect of diabetes on colorectal prognosis in 2013, a series of large-scale long-term cohort studies has comprehensively reported the outcome effect estimates on the relationship between diabetes and colorectal prognosis, and their results were still consistent.MethodsWe carried out an extensive search strategy in multiple databases and conducted a meta-analysis on the effect of diabetes on colorectal prognosis, based on the included 36 cohort studies, which contained 2,299,012 subjects. In order to collect more data, besides conventional methods, we used the professional software to extract survival data from the Kaplan-Meier curves, and analyzed both the 5-year survival rate and survival risk in overall survival, cancer-specific survival, cardiovascular disease—specific survival, disease-free survival, and recurrence-free survival, to comprehensively reflect the effect of diabetes on colorectal prognosis.ResultsThe results found that compared to patients without diabetes, patients with diabetes will have a 5-year shorter survival in colorectal, colon and rectal cancer, with a 18%, 19% and 16% decreased in overall survival respectively. We also found similar results in cancer-specific survival, cardiovascular disease—specific survival, disease-free survival, and recurrence-free survival, but not all these results were significant. We performed the subgroup analysis and sensitivity analysis to find the source of heterogeneity. Their results were similar to the overall results.ConclusionsOur meta-analysis suggested that diabetes had a negative effect on colorectal cancer in overall survival. More studies are still needed to confirm the relationship between diabetes and colorectal prognosis in cancer-specific survival, cardiovascular disease—specific survival, disease-free survival, and recurrence-free survival.